Nu-hydroxypenicillin amides



United States Patent 0 3,301,811 N-HYDROXYPENICILLIN AMIDES John C. Godfrey, Syracuse," N.Y., assignor to Bristol- Myers Company, New York, N.Y., a corporation of Delaware No Drawing. Filed Oct. 28, 1963, Ser. No. 319,502

9 Claims. (Cl. 260-306.7)

This invention relates to novel antibacterial agents and, more particularly, to 6-substituted-pe-nicillan-3 hydroX- amic acids and especially to the compounds which may be named N-hydroxypenicillin amides.

The compounds of the present invention are effective antibacterial agents against Gram-positive bacteria and are thus useful both in the laboratory, e.g. to remove such organisms when found as contaminants, and in therapy in man and animals.

There is thus provided, according to the present invention, the series of compounds having the formula NHOH wherein R and R may be hydrogen, alkyl, aralkyl, acyl, carboalkoxy, carbobenzoxy, carboaryloxy, carbamyl, substituted carb-amyl, arylsulfonyl or alkylsulfonyl; and the nontoxic, pharmaceutically acceptable salts thereof.

The preferred series of compounds is that of the formula in which R represents the side chain of any of the known penicillins, i.e. benzyl in the case of benzylpenicillins. It is this series which is named N-hydroxypenicillin amides or, more properly, 6-(a-substituted-acetamido)-penicillan- 3-hyclroxamic acids. Nontoxic, pharmaceutically acceptable salts of these acids are included in this preferred series.

Other known penicillins include those disclosed in US. Patents 2,941,995, 2,951,839, 2,996,501, 3,007,920, 3,025,- 290, 3,035,047, 3,040,032, 3,040,033, 3,041,332, 3,041,333, 3,043,831, 3,053,831, 3,071,575, 3,071,576, 3,082,204, 3,093,547 and 3,093,633 and in British patent specifications 874,414, 874,416, 876,516, 876,662, 877,120, 877,- 531, 878,233, 880,042, 880,400, 882,335, 888,110, 888,552, 889,066, 889,069, 889,070, 889,168, 889,231, 890,201, 891,279, 891,586, 891,938, 893,518, 894,247, 894,460, 896,072, 899,199, 900,666, 905,778, 906,383, 908,787, 914,419, 916,097, 916,204, 916,488, 920,176, 920,177, 920,300, 921,513, 922,278, 924,037 and 925,281 and in Belgian Patents 593,222, 595,171, 597,859, 602,494, 603,- 703, 609,039, 616,419 and 617,187 and in South African patent applications 60/2882, 60/3057, 60/3748, 61/1649, R61/275l, 62/54, 62/4920, 63/1612 and 63/2423.

Preferred compounds of the present invention are those of the formulae OH: C-CH:

wherein R represents hydrogen, phenyl, fluoro, chloro, bromo, iodo, hydroxy, (lower)alkanoyloxy including especially acetoxy or (lower)alkoxy; X represents oxygen or sulfur; R and R each represent hydrogen, phenyl, benzyl, phenethyl or (lower)alkyl; R represents (lower)- alkyl; R and R each represent (lower)alkyl, (lower)- alkylthio, benzylthio, cyclohexyl, cyclopentyl, cycloheptyl, benzyl, styryl, phenethyl, phenylpropyl, furyl, thienyl, naphthyl or Ar; R represents (lower)alkyla-rnino, di(lower)alkylamino, cycloalkylamino, having from 3 to 7 carbon atoms inclusive, allylamino, diallylamino, phenyl(lower)alkylamino, monpholino, lower(alkyDmorpholino, di(lower)alkylmorpholino, morpholino(l0wer)- alkylamino, pyrrolidino, (lower)alkylpyrrolidino, di- (lower)alkylpyrr0lidino, N,N-hexamethyleneimino, piperidino, lower(alkyl)piperidino, di(lower) alkylpiperidino, l,2,5,6-tetrahydropyridino, N-(lower)alkylpiperazino, N-

wherein R R and R are each a member selected from the group consisting of hydrogen, chloro, bromo, iodo, trifluoromethyl, phenyl, nitro, (lower) alkyl and (lower)- alkoxy but only one R group may represent phenyl; and nontoxic, pharmaceutically acceptable salts thereof.

The nontoxic, pharmaceutically acceptable salts include metallic salts such as sodium, potassium, calcium and aluminum, the ammonium salt and substituted ammonium salts, e.g. salts of such nontoxic amines as trialkylamines, including triethylamine, procaine, dibenzylamine, N- benzyl-beta-phenethylamine, l-ephenamine, N,N-dibenzylethylenediamine, dehydroabietylamine, N,N bis-dehydroabietylethylenediamine, N- (lower) alkylpiperidines, e.g. N-ethylpiperidine, N benzyldehydroa-bietylamine and other amines which have been used to form salts with benzylpenicillin. The term (lower)alkyl as used herein means both straight and branched chain aliphatic hydrocarbon radicals having from one to ten carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, amyl, hexyl, Z-ethylhexyl, heptyl, decyl, etc. Similarly, where the term (lower) is used as part of the description of another group, e.g. (lower)alkoxy it refers to the alkyl portion of such group which is therefore as described above in connection with (lower)- alkyl.

Preferred embodiments of the present invention are the restricted series of compounds of the following formulae 1 o=o-NoH |3=o NHOH wherein R represents (lower)alkyl and R is hydrogen or chloro;

wherein R represents (lower)alkyl;

wherein R is (lower)alkyl; and

wherein R is (lower)alkyl; and-the individual compounds of the following formulae 0 II c NHOH OO H

| 0 S CH3 OCH;

The starting material used in the process of the present invention is the acid chloride having the formula wherein R and R have the meaning set forth above or its functional equivalent as an acylating agent for the basic amino group of hydroxylamine. Such equivalents include the corresponding carboxylic acid bromides, acid anhydrides and mixed anhydrides with other carboxylic acids, including monoesters, and particularly lower aliphatic esters, of carbonic acid. In addition, an acid azide or an active ester or thioester (e.g. with p-nitrophenol, thiophenol, thioacetic acid) may be used or the penicillin free acid itself may'be coupled with hydroxylamine by the use of a carbodiimide reagent [cf. Sheehan and Hess, J. Amer. Chem. Soc., 77, 1067 (1955)].

A preferred starting material is a mixed anhydride of a penicillin with another carboxylic acid, including a monoester, and particularly a lower aliphatic ester, of carbonic acid.

Another preferred starting material is the acid halide of a penicillin which may be obtained by any of the standard methods which are known for producing such acid halides such as by the reaction of the penicillin with a thionyl halide; see British Patent 758,653.

It is preferred to conduct the reaction of the penicillin with thionyl halide in the presence of a solvent such as methylene chloride. Other solvents may also be used which will not deleteriously affect the reaction or the penicillin acid halide produced by the reaction. Reagents other than thionyl halides which are known to react with a carboxyl group to produce the corresponding acid halide may also be used. Since the reaction of thionyl halide with penicillin results in the liberation of hydrogen halide, it is preferred to conduct the reaction in the pres ence of an approximately equimolar amount of hydrogen halide acceptor such as pyridine or another tertiary amine. The temperature at which the reaction to form the penicillin acid halide is conducted is not critical and will depend to a large extent upon the nature of the reagent used to form the acid halide. When the reagent is thionyl chloride, it is preferred to conduct the reaction at below 0 C., e.g. at between about -40 C. and about 0 C. The proportions of the reactants are not critical as long as the thionyl chloride is used in excess. It is preferred to use from about one to two moles of thionyl chloride per mole of penicillin. After the reaction has proceeded to completion, the penicillin acid halide may be diluted with anhydrous ether and recovered as a fiuffy solid product by evaporation of the solvents in vacuo at 30-40 C. Alternatively, if the subsequent reaction is to be conducted in methylene chloride, the acid halide need not be isolated.

The penicillin acid halide is then reacted with hydroxylamine. This reaction is preferably conducted in a nonreactive solvent such as methylene chloride. Although the temperature of the reaction is not critical, it is preferred to conduct this reaction at between about 40 C. and room temperature (i.e. about 25 C.). Also, the proportions of reactants are not critical. It is preferred to use an excess of hydroxylamine in order to insure completeness of the reaction and to secure optimum yields. Thus, from about one to three moles of hydroxylamine is generally used for each mole of penicillin acid halide.

After the reaction is complete, the solvent may be removed and the product recrystallized from a solvent to obtain the pure penicillan-3-hydroxamic acid.

Another method which may be used to obtain the compounds of the present invention involves the reaction of hydroxylamine with a mixed anhydride of the penicillin. The production of mixed anhydrides of carboxylic acids is known. Briefly, the acid is treated with enough base, such as triethylamine, to form the salt and then with a reagent such as an alkyl chlorocarbonate or an organo sulfonyl chloride to form the mixed anhydride. The following equations exemplify this reaction O OlCOzCzHs 4% II Rom OCOCzlls wherein R and R may be radicals as previously described; M is a cation such as potassium, sodium or the triethylamino radical; and Y represents an alkyl carbonate or an organo (preferably alkyl or aryl) sulfonyl group i.e., Y may be, for example, -COOCH CH soi-om or --SO CH The reaction is preferably conducted in the presence of a non-reactive solvent such as methylene chloride. The reaction conditions may vary widely and are not critical. Thus, the temperature may range from about -30 C. up to the reflux temperature of the solution. The proportions may also be varied widely. It is preferred to use from one to two moles of the anhydride forming reagent per mole of penicillin salt.

After the mixed anhydride of the penicillin has been prepared, it is reacted with 'hydroxylamine. It is preferred that the reaction be conducted in the presence of a solvent such as methylene chloride. The temperature at which the reaction is conducted may vary between about 40 C. and the reflux temperature of the solution. The proportions of reactants may also be varied widely. It is preferred that from about one-half to two moles of hydroxylamine per mole of the penicillin mixed anhydride be used. After the reaction is complete, pure penicillan-3-hydroxamic acid may be recovered by removal of the solvent and recrystallization of the product.

There is thus provided by the present invention a process of reacting an acid chloride of the formula 1?) /S\ /CH3 R N-H0H (JCH3 wherein R and 'R may be hydrogen, alkyl, aralkyl, acyl, carboa-lkoxy, canbobenzoxy, carboaryloxy, carbamyl, substituted carbamyl, arylsul'fonyl or alkylsulfonyl or the functional equivalent of said acid chloride as an acylating agent with hydroxylamine to produce a penicillan-3-hydroxamic acid of the formula NHOH or a nontoxic pharmaceutically acceptable salt thereof. More specifically, there is provided by the present invention a process of reacting in an inert solvent at about 40 C. to 30 C. about 0.3-2.0 moles (per mole of hydroxylamine) of an acid chloride of the formula wherein R and R may be hydrogen, alkyl, aralkyl, acyl, carboalkoxy, carbobenzoxy, carboaryloxy, cahbamyl, substituted carbarnyl, arylsul'fonyl or alkylsul fonyl or the functional equivalent of said acid chloride as' an acylating agent with hydroxylam'ine to produce a penicillan-3-hydroxamic acid of the formula or a nontoxic pharmaceutically acceptable salt thereof.

A preferred embodiment of the present invention is the process of reacting a penicillin acid chloride or its functional equivalent as an acylatin'g agent wit-h hydroxylamine to produce the corresponding penicillan-3-hydroxamic acid or a nontoxic pharmaceutically acceptable salt thereof.

The compounds of the present invention are useful as nutritional supplements in animal feeds and as agents for the treatment of mastitis in cattle.

'0 0 The following examples will serve to illustrate the present invention but are not construed as limiting it thereto.

6 (a-phenoxypropionamido)-penicillan 3 hydroxamic acid, triethylamine salt.-A mixture of 13.8 g. of triethylamine hydrochloride (0.100 mole), 350 ml. of methylene chloride and 40.3 g. of potassium phenethicillin was stirred at 25 C. :for one-half hour to complete the metathesis to triethylammonium phenethicillin. The solution was cooled to 0 C. and 9.7 ml. of ethyl chloroformate was added slowly and the solution was stirred for 20 minutes at 0 C. to form the mixed anhydride. Then a solution of 6.95 g. (0.100 mole) of hydrox'ylamine hydrochloride and ml. of dry triethylamine in 400 ml. of methylene chloride was added at such a rate that the temperature did not rise above 0 C. The resulting solution of the product was stirred at 0 C. for 17 hours and filtered through diatomaceous earth. The filtrate was extracted with two 200 :ml. portions of a 3.25% solution of sodium bicarbonate in Water, and then with 150 ml. of water. The combined aqueous extracts were washed with 150 ml. of ether, which was added to the methylene chloride solution. The methylene chloride-ether solution was dried over sodium sulfate at 25 C. for two hours, filtered and dried by distilling off the solvent at 33 C. and then by adding and distilling off two 150 ml. portions of ethyl acetate. The residue was dissolved in ml. of ethyl acetate and precipitated as a filterable solid by pouring into 25 liters of lower alkanes (Skellysoive B). The yield was 18 g. (37%) of 6-(a-phenoxypropionamido)-pencillan-3-hydroxamic acid, triethylamine salt as an otf-white solid which had an indefinite decomposition range above 100 C. Its infrared spectrum supported the assigned structure and a ferric chloride test in ethanol gave a deep red brown color. The substance was insoluble in dilute sodium bicarbonate solution but dissolved in dilute sodium hydroxide with immediate release of triethylamine.

Analysis.-Calcd. for C H N O S-C H N: C, 57.5; H, 7.55. Found: C, 58.5; H, 7.10.

This product was found to inhibit Staph. aureus Smith at 0.8 mcg./ml., to inhibit Staph. aureus BX-l633, which is highly reistant to benzylpenicillin, at 6.25 meg/ml. and to exhibit versus Staph. aureus Smith in mice a CD of 5.4-19 -mgm./kg. upon intramuscular injection (compared to a CD range of 9.4-23 mgm/lcg. for benzylpenicillin).

6-(2,6'-dimeth0xybenzamido)-penicillan 3 hydroxamic acid .Sodium 6- 2',6'-dimethoxybenzamido penicillanate mon-ohydrate (42.0 g., 0.100 mole) and triethylamine hydrochloride (21.0 g., 0.15 mole) were stirred 45 minutes at 25 C. in 400 ml. methylene chloride to give the triethylamine salt. After removing the methylene chloride by distillation in vacuo, the residue was dissolved and suspended in a mixture of 300 ml. dioxane and 50 ml. methylene chloride and cooled to 3 C. There was then added 9.52 ml. (0.100 mole) ethyl chloroformate; the reaction mixture was stirred ten minutes at 3 to 5 C. to form the mixed anhydride.

The 'hydroxylami-ne reagent was prepared by stirring hydroxylamine hydrochloride (7.65 g., 0.110 mole) in 200 ml. dioxane for 30 minutes at 25 C.; after cooling until the dioxane began to freeze there was added 15.5 ml; (0.110 mole) 'triet-hylamine and then 26 ml. deionized water which dissolved nearly .all the precipitate. This solution was cooled toincipient freezing and added all at once to the solution of the mixed a'nhydride prepared above.

Evolution of gas began immediately and continuedfor several minutes. The reaction mixture containing the product, 6 (2',6-dimethoxybenzamido)-penicillan-3-hydroxamic acid, in solution was stirred at 5 C. for one hour and then at up to 12 C. for thirty minutes. After removing by filtration 38.8 g. solid (whichiwasa mixture of triethylamine hydrochloride and sodium chloride) the solvent was removed by flash distillation to leave the product as a gurn which was dissolved in ajmixture of 300 ml. methylene chloride and 200ml. ethyl acetate, extracted twice with 400 ml. water at about pH 7 and dried over Na SO Removal of the solvent by flash distillation and drying overnight over P in vacuo gave 28.0 g. product as a brittle, non hygroscopic, fiuify solid which exhibited the expected, characteristic infrared absorption spectrum, e.g., broad OHNH at 2.8-3.1 in tense betalactam at 5.605.62,u., weak absorption at 58 an amide at 6.01-6.09,u, and a second amide at-'6.60'.6.6 and ethereal.COC at 8.0 and 9.0

EXAMPLE 3 GIT;

6-phenylacetamido-penicillan 3 hydroxamic acid.A solution (No. 1) was prepared by adding 21.0 g. (0.15 mole) triethy-lamine hydrochloride and 37,25 g. (0.100 mole) potassium penicillin G to 350 ml. methylene chloride and stirring for one hour at room temperature to produce the triethylamine salt of benzylpenicillin.

Another solution (No. 2) was prepared by adding 6.95 g. (0.100 mole) hydroxylamine' hydrochloride and 42.3 ml. triethylamine (3 equiv.) to 100 ml. dimethylformamide at about 5 C. and adding water until most of the solid had dissolved.

Solution No. 1 was flash distilled in vacuo to remove the methylene chloride, 370 ml. dimethylfor-mamide was added and the solution was cooled to 5 C. Ethyl chloroformate (9.1 ml., 0.100 mole) was added all at once and the mixture was stirred for about ten minutes at 5 to 0 C. The evolution of carbon dioxidewas observed, and the mixed anhydride of benzylpenicillin was formed. To this solution, there was added all at once solution No. 2 of hydroxylamine. The mixture turned yellow and carbon dioxide Was evolved; the mixture was stirred for 30 minutes at 0 C. to form the desired product, 6-phenylacetamido-penicillan-3-hydroxamic acid.

The reaction mixture was poured into 3300 ml. icewater, filtered through diatomaceous earth and acidified to pH 2.0 to precipitate the product as a white solid which was collected by filtration, dried 'over P 0 in vacuo and found to weigh 18.6 g., to have an infrared absorption spectrum consistent with the assigned structure, to give a positive ferric chloride test, to decompose on heating to about 1101 15 C., to contain about one mole of solution of dimethylformamide.

Analysis.-Calcd. for C H N O S.C -H NO: C, 55.00; H, 5.48; N, =l2.13. Found: C, 54.25, 54.01; H, 5.84, 6.20; N, 11.78, 13.29.

The product was found to inhibit Staph. aureus Smith at 0.125 mcg./ml. and to exhibit versus Staph. aureus Smith in mice a CD of 1.3 to 11 mgrn./kg. upon intramuscular injection.

6-(5' methyl-3-phenyl-4-is0xazolecarboxamido)penicillan-3-hydr0 xamic acid.-Sodium oxacillin monohydrate (5-methyl-3-phenyl-4-isoxazolylpenicillin, 45.3 g., 0.100 mole) and triethylamine hydrochloride (21.0 g., 0.150 mole) were stirred for one hour at 25 C. in 400 ml. methylene chloride. After removing the methylene chloride by flash distillation in vacuo, there was added 300 ml. dioxane and 50 ml. methylene chloride. The solution was stirred for 10 minutes and then cooled to 4 C. Ethyl chloroformate (9.52 ml., 0.100 mole) was added and the resulting solution was stirred for 10 minutes to form the mixed anhydride.

A second solution was formed by stirring hyroxylamine hydrochloride (7.65 g., 0.110 mole) for 30 minutes at 25 C. in 200 ml. dioxane. The solution was then cooled in an ice-bath until the dioxane began to freeze and triethylamine (15.5 ml., 0.110 mole) and then Water (26 ml.) was added. The resulting solution of hydroxylamine was cooled to incipient freezing and added to the previously prepared solution of the mixed anhydr-ide of oxacillin. The reaction mixture was stirred for one hour as 5 C. The evolution of gas (carbon dioxide) was observed. The reaction mixture was stirred for one hour at 5 C. over 30 minutes and filtered (to remove triethylamine hydrochloride); the filtrate was flash distilled at 37 C. in vacuo, removing additional precipitation of triethylamine hydrochloride, to leave the product, 6-(S'-methyl- 3'-pheny1-4-isoxazolecarboxamido)penicillan 3 hydroxamic acid, as a gummy solid which was dissolved in a mixture of 30 0 ml. methylene chloride and 200 ml. ethyl acetate. This solution was extracted twice with 400 ml. water at about pM 7. The solvent phase was dried over Na 'SO and filtered; distillation in vacuo removed the solvent to leave the product as a dry crystalline residue to which was added 1.4 ml. diethyl ether. The crystalline product 6- (5'-methyl-3 '-phenyl-4-isoxazolecarboxamido penicillan-3-hydroxamic acid, was collected by filtration and found to weigh 34.6 g. and to exhibit an infrared absorption spectrum consistent with its assigned structure, including a strong bet-a-lactam at 5.6, an amide at 6.05 and a second amide at 6.5'8-6.-62 microns.

A sample of the product (5 g.) was purified by dissolving it in a mixture of 65 ml. methylene chloride and 15 ml. ethyl acetate; this solution was extracted twice with ml. portions of 2N HCl and then twice with ml. portions of water. The solvent layer was dried over Na SO and the solvent was removed by flash distillation in vacuo to leave the purified product as a solid which was collected by filtration, washed with 300 ml. dry diethyl ether and found to weigh 3.0 g.

While various embodiments have been described in some detail, it will be understood that modifications can be made in the procedures described without departing from the scope of the invention. Certain agents, compounds, or mixtures (e.g. acids, bases, solvents, and the like) and other details described or equivalent to those described in relation to one procedure may be employed in connection with other procedures.

I claim:

1. A member selected from the group consisting of a compound of the formula in which R represents the side chain of a penicillin, and the nontoxic pharmaceutically acceptable salts thereof.

'1 1 2. A member selected from the group consisting of a compound selected from the group consisting of hydroxamic acids having the formulae s 0m Il AroH0-NH0H0H 0-0111 o=CN-0H0=o NHO H wherein R represents a member selected from the group consisting of hydrogen, phenyl, fluoro, chloro, bromo, iodo, hydroxy, (lower)alkanoyloxy and (lower)alkoxy; X represents a member selected from the group consisting of oxygen and sulfur; R and R each represent a member selected from the group consisting of hydrogen, phenyl, and (lower) alkyl; R represents (lower)alkyl; l and R each represent a member selected from the group consisting of (lower) alkyl and Ar and at least one of R and R represents (lower)alkyl;' R represents a member selected from the group consisting of (lower)alkylamino, di(lower)'alkylamino, cycloalkylamino having from 3 to 7 carbon atoms inclusive, allyamino, diallylamino, phenyl(lower)alkylamin0, morpholino, lower- (alkyl)morpholino, di(lower)alkylmorpholino, morpholino(lower)alkylamino, pyrrolidino, (lower)alkylpyrrolidino, di(lower)alkylpyrrolidino, N,N hexarnethyleneimino, piperidino, lower(alkyl)piperidino, di(lower)- alkylpiperidino, 1,'2,5,6 tetrahydropyridino, N-(lower)- alkylpiperazino, N phenylpiperazino, N (lower)alkyl- (lower)alkylpiperazino, N-(lower)alkyl di(lower)al'kylpiperaz'ino, furfurylamino, tetrahydrofur furylamino, N- (lower)a1kyl-N furfurylamino, N alkyl-N-anilino and (lower)alkoxyanilino; Z Z and Z each represent a member selected from thegroup consisting of (lower)- alkyl and the monovalent radical of the 'formula wherein R R and R are each hydrogen, chloro, bromo, iodo, trifluoromethyl, nitro, (lower)alkyl and (lower)alkoxy; R represents a member selected from the group consisting of (lower)alkyl, (lower)cycloall yl, naphthyl, benzyl and phenethyl; and Ar represents the rnonovalent radical of the formula wherein R R and R are each'a member selected'from the group consisting of hydrogen, chloro, bromo, iodo,

trifiuoromethyl, phenyl, nitro, (lower)alkyl and (lower)- alkoxy but only one R group may represent phenyl; and

nontoxic pharmaceutically accept-able salts thereof.

3. YA compound of the formula O QT amaor N I I I fi CH3 wherein R represents (1ower)a1ky1;

NHOH O'i)R O=CN-CHC=O 9. A member selected from the group consisting of 0 compounds of the formulae wherein R is (1ower)a1ky1; and

s CH 0CI-I.CNH-Gl-IOII CCH; 1| 3 1 l I ONHOHCH o-om R O=CNCHO=O 0=oN 0H0=0 NHOH NHOH wherein R re resents lowe alk 1; p r) y wherein R is (lower)a1kyl; and nontoxic, pharmaceuti- R2 0 S 0 H3 cally acceptable salts thereof.

References Cited by the Examiner N UNITED STATES PATENTS \O/ NHOH 2,593,852 4/1952 Cooper 260--239.1 wherein R represents (1:oWer)a-1ky1 and R is hydrogen 3,09 ,620 6/ 1963 SetO 260239.1 or chloro; 3,144,445 8/1964 Graut et al 260239.1 n S CH3 3,177,203 4/1965 Goldberg et a1. 26O--239.1 3,192,198 4/1965 Nayler et a1 260-239.1 R1- CNH-GH-C 1-1 0c1-r5 II I I OTHER REFERENCES N C=C-NGHC=O 2 I T Youngdale et a1., J-ourn. Medicinal Chemistry, vol. 7,

R Nlofi pp. 415-427, July 1964.

B NICHOLAS S. RIZZO, Primary Examiner.

wherein R is (lower)alky1 and R is hydrogen or chloro; J. W. ADAMS, Assistant Examiner. 

1. A MEMBER SELECTED FROM THE GROUP CONSISTING OF A COMPOUND OF THE FORMULA 